1. Field of the Invention
The present invention relates to cationic lipophilic complexes having utility as myocardial and hepatobiliary imaging agents.
2. Description of the Prior Art
In recent years diagnostic nuclear medicine has proven to be of enormous value to the medical community. Procedures for imaging, and therefore detecting abnormalities in the brain, liver, lungs, bones, and the like, have been well developed and are routinely used. These procedures are based on the tendency of the body to concentrate some chemical form of a particular gamma ray emitting isotope in the organ of interest; subsequent scanning of the organ with a gamma ray camera provides an image of the organ from which diagnostic information can be obtained. It is clear that the radioisotope with optimum nuclear properties (half-life, gamma ray energy, and the like) for medical gamma ray scanning is .sup.99m Tc. It is therefore desirable to develop various chemical forms of Tc that will (a) concentrate in organs for which no satisfactory imaging agent has yet been found and/or (b) show greater organ specificity than the imaging agents currently available.
The metastable isotope Tc-99m has a 6 hour half-life and an emission spectrum, 99% gamma radiation at 140 KeV, which is well suited for techniques of diagnostic nuclear medicine. Tc-99m has a high specific activity, 5.28.times.10.sup.9 millicuries per gram and a convenient rapid rate of decay; whereas its daughter product, Tc-99, has a specific activity which is almost 9 orders of magnitude lower and a half-life which is roughly 8 orders of magnitude longer. In recent years, Tc-99m has become readily available in hsopitals through the use of selective elution from a so-called molybdenum-99 (Mo-99) generator. The isotope Mo-99 produces Tc-99m as a radioactive decay product. (See for example, Jackson et al, U.S. Pat. No. 4,031,198, column 1).
The lack of efficaceous 99m-Tc myocardial imaging agents is probably the most important problem facing nuclear medicine today. Agents capable of visualizing myocardial infarcts would be especially useful in the clinic. There are two types of myocardial imaging agents: (1) The "positive" agents which accumulate in the infarcted area and therefore visualize the infarct as a "hot" spot of radioactivity on a relatively "cold" background of normal tissue. There are several "positive" 99m-Tc agents in current use, including 99m-Tc-pyrophosphate and 99m-Tc-HEDP; (Poe, N. D., Semin. Nucl. Med 7, 7-14 (1977): Buja, L. M. et al, J. Clin. Invest. 60. 724-740 (1977); Davis, M. A., et al, J. Nucl. Med., 17, 911-917 (1976); Wakat, M. A., et al, ibid, 21, 203-306 (1980)); (2) The "negative" agents which accumulate in the normal heart and therefore visualize the infarct as a "cold" area on a relatively "hot" background of normal tissue. There is currently no 99m-Tc "negative" imaging agent available. The agent used clinically is 201-Tl which is expensive, has a photo-peak that is low for optimum imaging, and provides a low count rate per dose. The replacement of 201-Tl with a 99m-Tc agent is a major quest in nuclear medicine.
The use of 99m-Tc radiopharmaceuticals for hepatobiliary imaging is well known in the art. By hepatobiliary imaging agent is meant a radiopharmaceutical which clears the bloodstream after a few minutes, accumulates in the liver and is subsequently secreted by the liver into the bile, gallbladder, common bile duct, and intestines. There has been a strong belief in the art that efficient hepatobiliary imaging agents have to be anionic. Thus, Firnau (European Journal of Nuclear Medicine, vol. 1, 137-139 (1976)) reviewed several references which disclose Tc-99m hepatobiliary imaging agents, and concluded that an absolute structural requirement for a substance to be excreted by the liver is that it be an organic anion. Firnau states that the reason for gallbladder and bile duct imaging in the Tc-99m chelates of the prior art, is their ability to quickly pass through the liver, this ability being rather unspecific and common to all organic anions.
This prejudice in the art towards the use of anionic lipophilic complexes of 99m-Tc appears to be born out by other work in this area. Loberg et al, U.S. Pat. No. 4,017,596 disclose liver-clearing chelates of 99m-Tc, wherein the chelating agents are substituted iminodiacetic acids and 8-hydroxyquinolines. These complexes are anionic. Loberg et al (International Journal of Applied Radiation and Isotopes, 1978, vol. 29, pp. 167-173) disclose technetium 99m-labeled N-(2,6-dimethylphenylcarbamoyl methyl)-iminodiacetic acid (Tc-HIDA) and its potential use as a radiopharmaceutical. Loberg et al (in Abstract: Society of Nuclear Medicine, 23rd Annual Meeting, 1976) demonstrate that this Tc-HIDA is an anionic monomer containing two HIDA ligands per Tc center. Winchell et al, U.S. Pat. No. 3,928,552 disclose a hepatobiliary radiopharmaceutical comprising 2-mercaptoisobutyric acid, chelating reduced technetium-99m. The aforementioned review article by Firnau (Eur. J. of Nuclear Medicine, 1, 137-139 (1976)) indicates that this radiopharmaceutical of Winchell et al is anionic. Jackson et al, U.S. Pat. No. 4,031,198 disclose a radiopharmaceutical for imaging the liver, labeled with technetium-99m, which includes a complexing agent which is a lipophilic mercaptan or thioketal. The mercaptan or thioketal complexes in this reference fall within the general type of anionic complexes discussed in the aforementioned Firnau review article.
Hunt et al, U.S. Pat. Nos. 4,088,747 and 4,091,088 discuss phenolic aminocarboxylic acid-liganded radiopharmaceuticals of technetium-99m. These phenolate/carboxylate type of ligands are known to be anionic, and the resulting pharmaceuticals of 99m-Tc fall within the general type of the review article by Firnau.
From this brief review of the prior art, it can be concluded that hepatobiliary imaging agents of technetium-99m currently in clinical use have anionic character. Because of this property however, they all suffer from a serious deficiency. High levels of bilirubin reduce, or eliminate, the ability of anionic agents to image the hepatobiliary system. Harvey, L. et al, J. Nucl. Med., 20, 310-313 (1979) have recently shown that this is because bilirubin is also anionic and therefore at high concentrations, it blocks the anion clearance mechanism of the liver and prevents anionic imaging agents from accumulating in the liver. This is a serious clinical problem since many jaundiced patients, with obvious hepatobiliary malfunction, have high bilirubin levels and therefore cannot be successfully imaged with anionic agents.
Nora, U.S. Pat. No. 4,058,593 provides the only example of a cationic radiopharmaceutical based on technetium-99m which accumulates, albeit to a very small extent, in the liver. Nora discloses bone-specific radiopharmaceuticals based on technetium-99m with a complexing agent selected from the group of stannous fluoride, metal triflurostannate and metal pentafluorodistannate. These agents however, are not lipophilic, and act predominantly by mechanical deposition in the liver. The agents are not hepatobiliary imaging agents since they do not clear the liver and are not secreted therefrom into the bile, gallbladder, common bile duct, and intestines. Thus, the liver deposition observed by Nora would be insufficient to obtain good hepatobiliary imaging.
A need therefore, continues to exist for myocardial imaging agents based on Tc-99m, especially so-called "negative" myocardial infarct imaging agents. A need also continues to exist for cationic complexes of Tc-99m which will deposit in the liver and will be secreted therefrom, thus providing efficient hepatobiliary imaging.